Silver nanoparticles modified nanocapsules for ultrasonically activated drug delivery

Novel ultrasound-sensitive nanocapsules were designed via layer-by-layer assembly (LbL) of polyelectrolytes for remote activated release of biomolecules/drug. Nanocapsules embedded with silver nanoparticles in the walls were synthesized by alternate assembly of poly(allylamine hydrochloride) (PAH) and dextran sulfate (DS) on silica template followed by nanoparticle synthesis and subsequent template removal thus yielding nanocapsules. The silver NPs were synthesized in situ within the capsule walls under controlled conditions. The nanocapsules were found to be well dispersed and the silver NPs were evenly distributed within the shell. FITC-dextran permeated easily into the capsules containing silver NP's due to the pores generated during the formation of NP's. When the loaded nanocapsules were sonicated, the presence of the silver NPs in the shell structure led to rupturing of the shell into smaller fragments thus releasing the FITC-dextran. Such nanocapsules have the potential to be used as drug delivery vehicles and offer the scope for further development in the areas of modern medicine, material science, and biochemistry.     

Lipid nanocapsules for intracellular drug delivery of anticancer drugs

As non-phagocytic eukaryotic cells can internalize particles < 1 microm in size, small size (25 to 110 nm) lipid nanocapsules (LNC) are proposed for the intracellular drug delivery of anticancer drugs to cancer cells. LNC of different diameters were loaded with etoposide or paclitaxel and subsequently tested for drug release kinetics and their efficiency to reduce cancer cell growth in cell culture. Relative high drug loads could be achieved and sustained drug release can be provided over a period of several days (etoposide) up to a few weeks (paclitaxel). While particle size exhibited only minor influences on the release kinetics, higher initial drug load led to a distinctly lower burst release. In a cancer cell culture model, etoposide or paclitaxel LNC showed a 4-fold or 40-fold higher efficiency, respectively than the drug solution while blank LNC were found to be less toxic than the pure drug at equivalent concentrations. The uptake and intracellular accumulation of LNC was confirmed by confocal laser scanning microscopy after fluorescence labeling of the nanocarriers. This nanoparticulate system is able to achieve efficient intracellular drug concentrations and seems to be therefore a promising therapeutic approach in cancer treatment.     

Controlled drug delivery system based on magnetic hollow spheres/polyelectrolyte multilayer core-shell structure

A novel controlled drug delivery system was fabricated by coating chitosan/PAA multilayer onto magnetic hollow spheres via a "Layer-by-Layer" (LBL) assembly approach. Cefradine was used as a model drug to evaluate the drug release characteristics of this core-shell hollow structure and the results show that it exhibits a sustained release of the drug and the release rate can be regulated by the pH environment of release medium. It is believed that this core-shell hollow structure, which combines the advantage of controlled delivery as well as magnetic targeting, has commendable potential in drug delivery therapeutics.     

基于layer-by-layer技术构建胆碱检测生物传感器酶电极的研究

基于层层累积自组装法将PDDA高分子材料和胆碱氧化酶逐层固定在高分子聚合膜PVS/PDDA修饰的电极表面,制备了电流型胆碱检测生物传感器.利用石英晶体微天平(QCM)分别分析了PDDA和胆碱氧化酶的固定过程,结果表明酶的固定量可以得到有效控制.探讨了自组装膜层数、pH值、温度对传感器电流响应的影响.制备的生物传感器在胆碱浓度为5×10-7～1×10-4 mol/L的范围内对胆碱有良好的线性响应,响应时间为10 s,检出限为5×10-7 mol/L.传感器的稳定性好,30天时的响应值仍保持90%.     

Hemocompatibility of layer-by-layer hyaluronic acid/heparin nanostructure coating on stainless steel for cardiovascular stents and its use for drug delivery

In order to develop drug-eluting cardiovascular stents, stainless steel (SUS316L) sheets were coated with hyaluronic acid (HA) and heparin (HEP), and their in vitro characteristics and drug release pattern were investigated. The surface of stainless steel (SS) was treated with nitric acid and followed by anchoring aminotrimethoxysilane (ATMS), then a nanolayer of HA was covalently immobilized onto the surface. Heparin was then covalently bonded to the HA-immobilized SS substrate. After repeating 1 to 5 cycles, 1 to 5 layers polyelectrolyte complex (PEC) nanobrush of HA/HEP were resulted with the thickness ranging from 280 to 630 nm (measured with ellipsometry). A model drug (sirolimus) was loaded in the HA/HEP layers at a density ranging from 1.02 to 3.12 microg/cm2. The SS-ATMS-HA-HEP substrates were evidenced by X-ray photoelectron spectroscope (XPS), contact angle, and AFM measurement. The effect of this surface modification on the coagulation time of the resulting SS substrates was investigated. The results show that the multilayer HA/HEP stainless steel would exhibit higher anticoagulant activity than pure SS substrates. In addition, the results of the in vitro drug delivery study showed that release of sirolimus from the 5-layer-HA-HEP stainless steel was able to maintain more than 30 days. Thus layer-by-layer HA/HEP PEC can improve the hemocompatibility of SS surface and control the drug released rate by multiple layers of HA/HEP PEC. These results indicate that the multi-layer HA/HEP PEC coated stainless steel would be suitable for drug eluting stents.     

Polymeric nanostructures for drug delivery applications based on Pluronic copolymer systems

The first part of this article reviewed the applications of nanostructures derived from Pluronic block copolymers that have potentials in the field of biomedical sciences. Pluronic block copolymers are used not only in drug delivery systems but also in gene and cancer therapies. In the second part, the chemical modifications of Pluronic copolymers and their applications in biomedical science were reviewed. Chemical modifications of Pluronic copolymers not only improve the properties of the polymers but they also impart more attractive properties to the block copolymers. The common systems used to modify Pluronic copolymers are polyacrylic acids, polybases, and biodegradable polyesters. Pluronics were also modified at both ends with functional groups to improve the mechanical properties of hydrogels.     

Development of delayed-release proliposomes tablets for oral protein drug delivery

Context: One among many attempts to improve oral protein drug delivery was utilizing the colloidal drug carriers particularly liposomes.

Objective: The purpose was to develop proliposomes of bovine serum albumin (BSA) in the form of granules and delayed-release tablets by using simple tablet manufacturing process.

Materials and methods: BSA proliposomes granules were prepared by spraying 7:3 (w/w) – lecithin:cholesterol solution mixture onto BSA-mannitol granules rotating in a glass coating pan. BSA proliposomes granules were directly compressed into tablets and subsequently coated with Eudragit^® L100 film. The physical properties and stability in gastrointestinal fluids of delayed-release BSA proliposomes tablets as well as reconstituted liposomes were assessed.

Results: The BSA proliposomes tablets disintegrated readily and the obtained reconstituted BSA liposomes exhibited multilamellar vesicles, the size and entrapment efficiency of which were around 2–3 µm and 10–14%, respectively. The delayed-release BSA proliposomes tablets were found to be relatively stable in United States Pharmacopoeia (USP) simulated gastric and intestinal fluids. Increase in amount of BSA in granules resulted in the increase in entrapment efficiency and loading capacity.

Discussion: The Fourier transform infrared spectroscopy (FTIR) results indicated increase in α-helix structure of BSA entrapped in liposomes. ³¹P phosphorous nuclear magnetic resonance spectroscopy (³¹P-NMR) spectrum indicated interaction between BSA molecules and phosphoric acid polar groups of bilayers membrane.

Conclusion: The delayed-release BSA proliposomes tablets developed could completely be reconstituted into liposomes with sufficient resistance to the hostile environment in gastrointestinal tract.     

Advanced materials for drug delivery and biosensors based on magnetic label detection

Many traditional magnetic materials are not suitable for the increasing demands of microsensors for environmental control, biomedical applications, drug delivery, and homeland security. The design of magnetic biosensors can be based on different types of magnetic effects. The detection principles are measurements of the resistance, impedance, etc. in the absence and presence of magnetic nanoparticles. Variations in the measured parameters can be associated with either many individual molecular recognition events or with a specific uptake. Magnetic materials which could be used in magnetoimpedance based biosensors have been studied both for the sensitive element and for magnetic label. The self-assembling processes were observed in perpendicular field for different concentrations of the Dynabeads® M-480. Magnetic field controlled assembly is proposed for designing new composite materials which can be also useful to study the properties of the separate particles. The morphology of the particle agglomerates and dipolar chains in the external field can be controlled by using simultaneously two different suspensions of magnetic particles. A new concept is to define synergetic combinations of two or more nanostructures for the best performance.     

Controlled drug delivery systems based on thiolated chitosan microspheres

The aim of the present study was to verify the potential of chitosan-thio-butyl-amidine (TBA) microspheres as carrier systems for controlled drug delivery. In this study microspheres were prepared utilizing water in oil (w/o) emulsification solvent evaporation technique. A concentration of 0.5% of chitosan-TBA conjugate displaying 100 µM thiol groups per gram polymer was used in the aqueous phase of the emulsion in order to prepare microspheres. The obtained non-aggregated free-flowing microspheres were examined with conventional light microscope as well as scanning electron microscopy (SEM). The microscopic images indicated that the prepared chitosan-TBA microspheres were of spherical shape and smooth surface while microparticles obtained from the unmodified chitosan were of porous structure and non-spherical shape. Particle size distribution was determined to be in the range from 1 to 59 µm. The free thiol group content of chitosan-TBA microspheres prepared with an aqueous phase of pH 2, 5, and 6.5 were determined to be 71.4, 49.4, and 8.2 µM/g polymer, respectively. Furthermore, results attained from in vitro release studies with fluorescein isothiocyanate labelled dextran (FITC-dextran) loaded chitosan-TBA microspheres showed a controlled release rate for more than three hours while the control reached the maximum peak level of release already within an hour. According to these results, chitosan-TBA microspheres seem to be a promising tool in transmucosal drug delivery for poorly absorbed therapeutic agents.     

Oral controlled drug delivery systems based on microporous polymers

Microporous polypropylene (PP) powder shows excellent properties for tabletting. Oral controlled release delivery systems were made by simply blending with drug and compressing to make both matrix and coated tablets. To prevent wetting problems and food interactions, sodium lauryl sulphate (SLS) was adsorbed prior to tabletting on the surface of the microporous PP. In order to reveal possible dosage form-food interactions a new and simple food interaction model (slight modification of the USP XX paddle method) is proposed to standardize both in vitro and in vivo testing procedures. The PP coated oxprenolol tablets show no food interactions when tested in vitro in the food simulation mixture. The same liquid food was used in the in vivo study. The PP coated oxprenolol tablets were given to six male volunteers with and without the food. The absorption profiles, which were calculated by numerical deconvolution, showed hardly any food interactions in vivo. The absolute bioavailability at 12 hours was 38±19% on an empty stomach and 37±20 for the food experiment. The developed coated tablets are able to control the release of oxprenolol at least 12 hours both with and without concomitant food intake. Their bioavailability is comparable to different OROS formulations of oxprenolol controlled release systems based on microporous PP are not only highly effective ones but also low cost formulation products.     

Oral controlled drug delivery systems based on microporous polymers

Abstract

Microporous polypropylene (PP) powder shows excellent properties for tabletting. Oral controlled release delivery systems were made by simply blending with drug and compressing to make both matrix and coated tablets. To prevent wetting problems and food interactions, sodium lauryl sulphate (SLS) was adsorbed prior to tabletting on the surface of the microporous PP. In order to reveal possible dosage form-food interactions a new and simple food interaction model (slight modification of the USP XX paddle method) is proposed to standardize both in vitro and in vivo testing procedures. The PP coated oxprenolol tablets show no food interactions when tested in vitro in the food simulation mixture. The same liquid food was used in the in vivo study. The PP coated oxprenolol tablets were given to six male volunteers with and without the food. The absorption profiles, which were calculated by numerical deconvolution, showed hardly any food interactions in vivo. The absolute bioavailability at 12 hours was 38±19% on an empty stomach and 37±20 for the food experiment. The developed coated tablets are able to control the release of oxprenolol at least 12 hours both with and without concomitant food intake. Their bioavailability is comparable to different OROS formulations of oxprenolol controlled release systems based on microporous PP are not only highly effective ones but also low cost formulation products.     

BioMEMS for drug delivery

Recent research into methods of using microelectromechanical systems (MEMS) technology for medical and biological applications has developed several interesting devices. This paper reviews various approaches to the use of MEMS for drug therapy, including devices based on microporous silicon, microneedles, micropumps, and microreservoirs. Microdevices can improve drug therapy because they allow precise and complex dosing, induce less pain, or increase compliance. Microneedles have been tested on humans, and the other drug delivery MEMS have shown promise in vitro and in vivo. Investigations into the use of microelectromechanical systems (MEMS) technology to produce microdevices for drug delivery have expanded recently. We present several different approaches to the use of microdevices for drug therapy and the current state of the field.     

Preparation of benznidazole pellets for immediate drug delivery using the extrusion spheronization technique

Abstract

Recent advances in the treatment of Chagas disease have followed combinations of drugs that act synergistically against infection, predominantly including benznidazole (BNZ) and azoles derivatives. Possible incompatibilities between these drugs, slow dissolution of BNZ and dose adjustment difficulties are technological obstacles to the development of multidrug formulations. Thus, in the present study, BNZ pellets were developed using extrusion spheronization for immediate drug delivery. Preformulation studies were then performed using thermal analysis and infrared spectroscopy and compatibility between the drug and selected excipients (polyethylene glycol 6000, sodium starch glycolate, microcrystalline cellulose and sodium croscarmellose) was investigated. No chemical decomposition of BNZ was observed, even in samples submitted to wet granulation and thermal stress. Subsequently, formulations were elaborated according to a simplex lattice experimental design using polyethylene glycol, sodium starch glycolate and sodium croscarmellose as disintegrating agents. In these experiments, BNZ pellets showed appropriate physicochemical characteristics, including high drug load capacity and excellent flow properties. The mixture experimental design allowed identification of adequate compositions of disintegrating agents and achieved rapid disintegration and dissolution of pellets. Optimum performance was achieved using polyethylene glycol and sodium croscarmellose at 5.0% w/w each. The present BNZ pellets are versatile alternatives to treat Chagas disease and provide insights into the preparation of multidrug systems.     

Surface-modified and conventional nanocapsules as novel formulations for parenteral delivery of halofantrine

The aim of this work was to develop a stable injectable formulation of the antimalarial drug halofantrine (Hf) based on nanocapsules (NC) prepared from biodegradable polymers with Miglyol 810N as the oily core. Poly(D,L-lactide) PLA and its copolymers with poly(ethyleneglycol) (PLA-PEG) were used together with the surfactants poloxamer 188 and lecithin to yield NC with different surface properties. Highly efficient loading of the free base form of Hf was obtained; zeta potential measurements indicated that a part of the associated Hf was at the NC surface, interacting with the lecithin. NC were 150-250 nm in diameter and more stable on storage than nanoemulsions formed from oil and lecithin without polymer. The most stable NC, showing minimal size changes and flocculation, were those with a high density of 20-kDa PEG chains covalently grafted at the surface. Hf release from NC occurred mainly by partition with the external medium. In PBS, even when Tween 80 was added, release was limited to 20% of the total content, whatever the formulation. Addition of serum to the medium allowed complete and rapid release from PLA NC stabilized with adsorbed poloxamer 188, because of the high affinity of Hf for lipoproteins. However, the presence of covalently grafted PEG chains at the surface limited release by providing a hydrophilic steric barrier at the particle surface. A dense coverage with long PEG chains provided the best reduction of release. Such systems could constitute a long-circulating intravenous formulation of Hf for treating severe malaria.     

Protein nanocapsules based vectors for efficient gene transfection

Gene therapy employs exogenous nucleic acids to treat genetic diseases and disorders.The insufficient cytosolic delivery of genetic materials remains a major hurdle for effective gene therapy.To address this challenge,we have designed and synthesized various cationic protein nanocapsules that can efficiently condense nucleic acids via self-assembly.Through systematically investigating the gene transfection efficiency of these nanocapsules as delivery vectors,we find that nanocapsules,which were synthesized with hydrolyzable polymers containing tertiary amine groups,afford the highest transfection efficiency(?80%),resulting in stable protein expression for over four days.The mechanistic study reveals that tertiary amine groups facilitate the endosomal escape of the nucleic acid-nanocapsule complexes after their cell internalization via endocytosis.The subsequent hydrolysis of the polymers triggers the cytosolic release of the nucleic acids,thereby prompting gene expression.Our results not only provide a new class of gene delivery vectors but also detail the parameters for future vector design.     

Feasibility of obtaining in situ nanocapsules through modified self-microemulsifying drug delivery systems. A new manufacturing approach for oral route administration

Nanocapsules (NCs) are submicron-sized core shell systems which present important advantages such as improvement of drug efficacy and bioavailability, prevention of drug degradation, and provision of controlled-release delivery. The available methods for NC production require expensive recovery and purification steps which compromised the morphology of NCs. Industrial applications of NCs have been avoided due to the aforementioned issues. In this study, we developed a new method based on a modified self-microemulsifying drug delivery system (SMEDDS) for in situ NCs production within the gastrointestinal tract. This new methodology does not require purification and recovery steps and can preserve the morphology and the functionality of NCs. The in situ formed NCs of Eudragit^® RL PO were compared with nanospheres (NEs) in order to obtain evidence of their core-shell structure. NCs presented a spherical morphology with a size of 126.2?±?13.1?nm, an ibuprofen encapsulation efficiency of 31.3% and a zeta-potential of 37.4?mV. Additionally, NC density and release profile (zero order) showed physical evidence of the feasibility of NCs in situ creation.     

Nanoparticles for intracellular-targeted drug delivery

Nanoparticles (NPs) are very promising for the intracellular delivery of anticancer and immunomodulatory drugs, stem cell differentiation biomolecules and cell activity modulators. Although initial studies in the area of intracellular drug delivery have been performed in the delivery of DNA, there is an increasing interest in the use of other molecules to modulate cell activity. Herein, we review the latest advances in the intracellular-targeted delivery of short interference RNA, proteins and small molecules using NPs. In most cases, the drugs act at different cellular organelles and therefore the drug-containing NPs should be directed to precise locations within the cell. This will lead to the desired magnitude and duration of the drug effects. The spatial control in the intracellular delivery might open new avenues to modulate cell activity while avoiding side-effects.